The microbes that help break down food actually tell the gut how best to do their job, according to a new study on mice at Duke.
The researchers said that microbes appear to be able to influence which gut genes are involved in the action, and in turn, this interaction can lead to a rearrangement of the epithelial cells lining the gut to match their diet.
“The gut is an exciting interface between an animal and the world in which it lives, and receives information from both diet and microbes,” said John Rawls, Ph.D., professor of molecular genomics and microbiology at Duke. and the director of the Duke Center for Microbiome.
The study appeared May 6 in an open access journal Cellular and molecular gastroenterology and hepatology.
To begin analyzing messages coming from microbes to gut cells, Duke’s researchers compared mice raised without any gut microbes and mice with a normal gut microbiome. The researchers focused on the cross-links between RNA transcription – DNA is copied into RNA – and proteins that turn this process on or off in the small intestine, where most of the absorption of fat and other nutrients takes place.
Although both microbial-free mice and normal mice were able to digest fatty acids in a high-fat diet, a striking discovery was that non-microbial animals used a completely different set of genes to combat high-fat foods.
“We were surprised to find that the genes that the intestinal epithelium uses to respond to fat are different depending on whether there are germs,” Rawls said.
Researchers have also seen that microbes can help the gut digest fats.
“This is a relatively consistent finding in many studies conducted in our lab and others that microbes do promote lipid uptake,” said Colin Likvar, Ph.D., senior researcher at Rawls Lab and the first author of the paper. “And it to some extent also affects systemic processes such as weight gain.”
Mice without microbes observed an increase in the activity of genes involved in the oxidation of fatty acids, literally burning fatty acids to provide fuel for intestinal cells.
“Usually, we think the gut just does its job of absorbing nutrients through the epithelium to share with the rest of the body, but the gut also needs to eat,” Rawls said. “So what we think happens in animals without germs is that the gut consumes more fat than it would if there were germs.”
And this may reflect differences in the composition of intestinal epithelial cells.
“There’s a bunch of recent work that shows that there’s a significant ability to change the big gut architecture, as well as individual genetic programs,” Likvar said. “There’s considerable plasticity in the gut. We mostly don’t understand that, but some of it is clarified in this article.”
The researchers focused their efforts on a transcription factor called HNF4-Alpha, which is known to regulate genes involved in lipid metabolism and genes that respond to microbes. “We thought it might be an interface or a cross between the interpretation of information coming either from microbial sources or from dietary fat,” Likvar said.
“It’s certainly difficult, but we seem to identify that HNF4-alpha is important for the simultaneous integration of multiple signals in the gut,” Liquar said.
“Because all the ways in which animals without microbes seem unusual, it teaches us for some reason about the great influence of the microbiome on what we consider ‘normal’ animal biology,” Rawls said.
This study was supported by the National Institutes of Health (R01-DK093399, P01-DK094779, R01-DK113123, R01-DK111857, R01-DK081426, P01-HL020948) and the Nuclear Receptor Conlasor U4URSAN 693 DK09774).
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